1. Field of the Invention
The present invention relates generally to the field of molecular biology and oncology. More particularly, it concerns methods for identifying and treating homologous recombination (HR) repair defective cancers.
2. Description of Related Art
Genomic instability is a hallmark of cancer cells (Hanahan and Weinberg, 2011). To maintain genomic stability and ensure high-fidelity transmission of genetic information, cells have evolved a complex mechanism to repair DNA double-strand breaks (DSBs), the most deleterious DNA lesions, in an error-free manner through homologous recombination (HR) (Moynahan and Jasin, 2010; San Filippo et al., 2008). As expected, HR-mediated DNA repair deficiency predisposes to cancer development (Levitt and Hickson, 2002). For instance, germline mutations in the tumor suppressors BRCA1 and BRCA2, two critical HR repair mediators, predispose to both breast and ovarian cancer (Jackson and Bartek, 2009; Scully and Livingston, 2000). However, HR-mediated DNA repair deficiency also sensitizes cancer cells to DNA-damage-inducing therapy such as radiation therapy and DNA-damage-based chemotherapy (Lord and Ashworth, 2012).
HRD also sensitizes cancer cells to DNA-damage-inducing therapy such as radiation therapy and cisplatin-based chemotherapy (Helleday et al., 2008; Lord and Ashworth, 2012). One of the most exciting recent therapeutic breakthroughs in cancer is identification of a synthetic lethal interaction between HR repair deficiency and poly(ADP-ribose) polymerase (PARP) inhibition (Bryant et al., 2005; Farmer et al., 2005). PARP inhibitors inhibit single-strand DNA repair, which leads to DSBs when DNA replication occurs. Normal cells can repair these DSBs. However, HR repair-deficient cancer cells cannot repair PARP-inhibitor-induced DSBs and die when treated with these drugs. Thus, PARP inhibitors can selectively target HR repair-deficient breast and ovarian cancer (Rehman et al., 2010). This concept holds great promise for effective treatment of BRCA1/2-associated breast and ovarian cancer and more broadly for all HR-repair-deficient tumors, particularly if practical and effective companion diagnostics able to robustly identify patients likely to benefit can be identified.
However, recent clinical trials of PARP inhibitors have shown disappointing results: For example, in the first phase I clinical trial of monotherapy with the oral PARP inhibitor olaparib, more than 35% of BRCA mutation carriers did not respond (Fong et al., 2009). In a phase II clinical study of olaparib in breast cancer patients with BRCA1/2 mutations, the response rate was 41%. Unfortunately, the progression-free survival times in the two cohorts were approximately 3.8 months and 5.7 months, suggesting that patients rapidly developed resistance (Tutt et al., 2010). In a similar phase II study in BRCA1/2 mutation carriers with recurrent ovarian cancer, the objective response rate was 33% (Audeh et al., 2010). Furthermore, there were no complete or partial responses to olaparib in 15 BRCA-negative patients with advanced-stage triple-negative breast cancer (TNBC), which has a molecular phenotype similar to that of BRCA1-deficient breast cancer (Gelmon et al., 2011). Thus only a portion of patients with BRCA1/2 aberrations respond and unfortunately responses are frequently short-lived. Thus a better approach able to predict patients likely to benefit or rational combination therapies with PARP inhibitors designed to prevent the emergence of resistance are needed to fulfill the promise of PARP inhibitors.